This invention relates to an improved process for preparing compounds of Formula II comprising coupling a compound of Formula IV with a compound of Formula V. This invention also relates to an improved process for preparing compounds of Formula III by coupling a compound of Formula IV with a compound of Formula V and subsequent deprotection of the resulting Prt-protected compound of Formula II.
Commonly assigned International Patent Application Publication No. WO97/24369, hereinafter referred to as the ""369 application, which is incorporated herein by reference, discloses certain growth hormone secretagogue compounds of Formula I, 
wherein the definitions of the variables are disclosed therein. Said compounds are disclosed in the ""369 application to have utility in treating, inter alia, osteoporosis.
Compounds of Formula II, 
are disclosed in the ""369 application as intermediates in a process to prepare the compounds of Formula III, 
which are within the scope of the disclosure of said international application.
The process disclosed in the ""369 application requires coupling a compound of Formula IV with a compound of Formula V. The first step in the coupling reaction is the reaction of a compound of Formula IV below with an organic amine to form the free base of the compound of Formula IV and the organic amine salt of tartaric acid. The next step in the disclosed process is a filtration step to remove the organic amine salt of tartaric acid. This was thought to be necessary to eliminate the possibility of reaction of tartaric acid with the compound of Formula IV under the coupling conditions. Due to the racemization of the 3a position of the pyrazolo[4,3-c]pyridine which occurs at room temperature, this filtration had to be performed cryogenically, i.e., at reduced temperatures. When operating the coupling reaction on a bulk scale, cryogenic filtration presents technical problems, e.g., entrainment, slow filtration, a need to use additional equipment and extra handling. This results in reduced yields of product. In the process of this invention, the cryogenic filtration is avoided, resulting in a more streamlined process and an improved chemical and optical yield.
This invention is directed to a process, designated Process A, of preparing a compound of Formula II, 
wherein:
R1 is xe2x80x94(C1-C10)alkyl optionally substituted with up to three fluoro atoms;
R2 is phenylmethyl or 2-pyridylmethyl;
R3 is xe2x80x94(C1-C5)alkyl-Oxe2x80x94(C0-C5)alkylphenyl, where the phenyl substituent in the definition of R3 is optionally substituted with up to three fluoro atoms; and
Prt is an amine protecting group, comprising:
a) mixing an appropriate chiral tartrate salt having the structure of Formula IV, 
wherein R1 and R2 are as defined above, and an organic amine in a reaction inert solvent at a temperature of about xe2x88x9268xc2x0 C. to about xe2x88x9240xc2x0 C. to form a slurry;
b) adding a compound of the Formula V, 
wherein R3 and Prt are as defined above, to said slurry to form a reaction mixture comprising the tartrate salt of the organic amine, the free base of a compound of Formula IV and a compound of the formula V; and
c) adding a coupling reagent to said reaction mixture to form a compound of Formula II.
A preferred process within Process A, designated Process B, is a process wherein said compound of Formula IV is suspended in said solvent prior to the addition of said organic amine.
A preferred process within Process B, designated Process C, is a process wherein said slurry is warmed to about xe2x88x9250xc2x0 C. prior to step b.
Another preferred process within Process A, designated Process D, is the process wherein: in step a, said organic amine is triethylamine; in step b, R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl and Prt is t-butyloxycarbonyl; and in step c, said coupling reagent is propane phosphonic acid anhydride.
A preferred process of Process D, designated Process E, is a process wherein R1 is methyl or 2,2,2-trifluoroethyl and R2 is phenylmethyl or 2-pyridylmethyl.
A preferred process of Process E is a process wherein the compound of Formula II selected from (1-(2-(1(R)-(2,4-difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester and (1-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester is prepared.
Another preferred process of Process E is a process wherein a compound of Formula IIA, 
is prepared.
Another preferred process of Process E is the process wherein a compound of Formula IIB, 
is prepared.
Another preferred process within Process B, designated Process F, is the process wherein: in step a, said organic amine is triethylamine; in step b, R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl and Prt is t-butyloxycarbonyl; and in step c, said coupling reagent is propane phosphonic acid anhydride.
A preferred process within Process F, designated Process G, is a process wherein R1 is methyl or 2,2,2-trifluoroethyl and R2 is phenylmethyl or 2-pyridylmethyl.
A preferred process within Process F is a process wherein the compound of Formula II selected from (1-(2-(1(R)-(2,4-difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester and (1-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester is prepared.
Another preferred process within Process F is a process wherein a compound of Formula IIA, 
is prepared.
Another preferred process within Process F is a process wherein a compound of Formula IIB, 
is prepared.
Another preferred process within Process C, designated Process H, is a process wherein: in step a, said organic amine is triethylamine; in step b, R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl and Prt is t-butyloxycarbonyl; and in step c, said coupling reagent is propane phosphonic acid anhydride.
A preferred process within Process H, designated Process I, wherein R1 is methyl or 2,2,2-trifluoroethyl and R2 is phenylmethyl or 2-pyridylmethyl.
A preferred process within Process I is a process wherein the compound of Formula II selected from (1-(2-(1(R)-(2,4-difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester and (1-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester is prepared.
Another preferred process within Process I is a process wherein a compound of Formula IIA, 
is prepared.
Another preferred process within Process I is a process wherein a compound of Formula IIB, 
is prepared.
This invention is also directed to a process, designated Process J, for preparing a compound of Formula III, 
wherein:
R1 is xe2x80x94(C1-C10)alkyl optionally substituted with up to three fluoro atoms;
R2 is phenylmethyl or 2-pyridylmethyl; and
R3 is xe2x80x94(C1-C5)alkyl-Oxe2x80x94(C0-C5)alkylphenyl, where the phenyl substituent in the definition of R3 is optionally substituted with up to three fluoro atoms, comprising:
a) mixing an appropriate chiral tartrate salt of the Formula IV, 
wherein R1 and R2 are as defined above, and an organic amine in a reaction inert solvent at a temperature of about xe2x88x9268xc2x0 C. to about xe2x88x9245xc2x0 C. to form a slurry;
b) adding a compound of the Formula V, 
wherein R3 and Prt are as defined above, to said slurry to form a reaction mixture comprising the tartrate salt of the organic amine, the free base of a compound of Formula IV and a compound of the Formula V;
c) adding a coupling reagent to said reaction mixture to form a compound of Formula II; and
d) reacting said compound of Formula II with a suitable deprotecting reagent to form a compound of Formula III.
A preferred process within Process J, designated Process K, is a process wherein said compound of Formula IV is suspended in said solvent prior to the addition of said organic amine and the additional step of warming said slurry to about xe2x88x9250xc2x0 C. to about xe2x88x9240xc2x0 C. is effected prior to step b.
A preferred process within Process K, designated Process L, is a process wherein said Prt is Boc and said Boc is removed by reacting said compound of Formula II with an acid.
A preferred process within Process L, designated Process M, is a process wherein said acid is methanesulfonic acid.
A preferred process within Process M, designated Process N, is a process wherein: R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b, said organic amine is triethylamine; and in step c), said coupling reagent is propane phosphonic acid anhydride.
A preferred process within Process N, designated Process O, is a process wherein R1 is methyl or 2,2,2-trifluoroethyl and R2 is phenylmethyl or 2-pyridylmethyl.
A preferred process within Process O is a process wherein said compound of Formula III selected from 2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl-1(R)-benzyloxylmethyl-2-oxo-ethyl]-isobutyramide and 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl-2-methyl-propionamide is prepared.
Another preferred process within Process O is a process wherein a compound of formula IIIA, 
is prepared.
Another preferred process within Process O is a process wherein a compound of formula IIIB, 
is prepared.
Another preferred process within Process L, designated Process P, is a process wherein said acid is trifluoroacetic acid.
A preferred process within Process P, designated Process R, is a process wherein: R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b, said organic amine is triethylamine; and in step c, said coupling reagent is propane phosphonic acid anhydride.
A preferred process within Process R, designated Process S, is a process wherein R1 is methyl or 2,2,2-trifluoroethyl and R2 is phenylmethyl or 2-pyridylmethyl.
A preferred process within Process S is a process wherein said compound of Formula III selected from 2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl-1(R)-benzyloxylmethyl-2-oxo-ethyl]-isobutyramide and 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl-2-methyl-propionamide is prepared.
Another preferred process within Process S is a process wherein a compound of formula IIIA, 
is prepared.
Another preferred process within Process S is a process wherein a compound of formula IIIB, 
is prepared.
Another preferred process within claim K, designated Process T, is a process wherein said Prt is Boc and said Boc is removed by reacting said compound of Formula II with an acid.
A preferred process within Process T, designated Process U, is a process wherein said acid is methanesulfonic acid.
A preferred process within Process U, designated Process V, is a process wherein: R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b, said organic amine is triethylamine; and in step c, said coupling reagent is propane phosphonic acid anhydride.
A preferred process within Process V, designated Process W, is a process wherein R1 is methyl or 2,2,2-trifluoroethyl and R2 is phenylmethyl or 2-pyridylmethyl.
A preferred process within Process W is a process wherein said compound of Formula III selected from 2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl-1(R)-benzyloxylmethyl-2-oxo-ethyl]-isobutyramide and 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl-2-methyl-propionamide is prepared.
Another preferred process within Process W is a process wherein a compound of formula IIIA, 
is prepared.
Another preferred process within Process W is a process wherein a compound of formula IIIB, 
is prepared.
Another preferred process within Process T, designated Process X, is a process wherein said acid is trifluoroacetic acid.
A preferred process within Process X, designated Process Y, is a process wherein: R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b), said organic amine is triethylamine; and in step c, said coupling reagent is propane phosphonic acid anhydride.
A preferred process within Process Y, designated Process Z, is a process wherein R1 is methyl or 2,2,2-trifluoroethyl and R2 is phenylmethyl or 2-pyridylmethyl.
A preferred process within Process Z is a process wherein said compound of Formula III selected from 2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl-1(R)-benzyloxylmethyl-2-oxo-ethyl]-isobutyramide and 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl-2-methyl-propionamide is prepared.
Another preferred process within Process Z is a process wherein a compound of formula IIIA, 
is prepared.
Another preferred process within Process Z is a process wherein a compound of formula IIIB, 
is prepared.
This invention is also directed to a process for preparing a compound of formula XX, 
comprising the following consecutive steps:
a) reacting said 4-oxo-piperidinecarboxylic acid methyl ester, hydrochloride with di-t-butyl-dicarbonate and triethylamine in isopropyl ether to form 4-oxo-1,3-piperidinedicarboxylic acid 1-(1-dimethylethyl) 3-methyl ester;
b) reacting said 4-oxo-1,3-piperidinedicarboxylic acid 1-(1-dimethylethyl) 3-methyl ester with benzyl bromide and potassium carbonate in tetrahydrofuran to form 4-oxo-(phenylmethyl)-1,3-piperidinedicarboxylic acid 1-(1-dimethylethyl)3-methyl ester;
c) reacting said 4-oxo-(phenylmethyl)-1,3-piperidinedicarboxylic acid 1-(1-dimethylethyl)3-methyl ester with methylhydrazine in acetic acid and methyl-t-butyl ether to form 2,3a,4,5,6,7-hexahydro-2-methyl-3-oxo-3a-(phenylmethyl)-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid 1,1-dimethylethyl ester; and
d) reacting said 2,3a,4,5,6,7-hexahydro-2-methyl-3-oxo-3a-(phenylmethyl)-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid 1,1-dimethylethyl ester with trifluoroacetic acid to form (3aR)-2,3a,4,5,6,7-hexahydro-2-methyl-3a-(phenylmethyl)-3H-pyrazolo[4,3-c]pyridin-3-one;
e) reacting said (3aR)-2,3a,4,5,6,7-hexahydro-2-methyl-3a-(phenylmethyl)-3H-pyrazolo[4,3-c]pyridin-3-one with L-tartaric acid in acetone and water to form said L-tartrate salt of formula XX.
This invention is particularly directed to a process as set forth in the immediately preceding paragraph wherein said L-tartaric acid is added without isolating said (3aR)-2,3a,4,5,6,7-hexahydro-2-methyl-3a-(phenylmethyl)-3H-pyrazolo[4,3-c]pyridin-3-one. In particular, the compound of formula XX is isolated as a dihydrate. The desired crystal form is isolated upon cooling from an appropriate mixture of solvents.
This invention is also directed to a polymorph of a dihydrate of a compound of formula XX: 
This invention is particularly directed to the polymorph having the atomic coordinates and equivalent isotropic displacement coefficients as set forth in Table 1. This invention is also particularly directed to the polymorph having the X-Ray crystal structure according to FIG. 1.